Study Finds p38 MAPK Drives Fibrotic Genes in Aging Lung Cells

Pharmacological inhibition of p38 MAPK reduced fibrotic markers in both lab-grown and patient-derived lung cells

Published on Mar. 11, 2026

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A new study published in the journal Aging-US has found that the stress-activated kinase p38 MAPK plays a key role in driving the expression of fibrotic genes in aging lung fibroblasts. The researchers showed that pharmacological inhibition of p38 MAPK reduced levels of profibrotic proteins like α-SMA and Col3A1 in both lab-grown fibroblasts and primary cells from patients with idiopathic pulmonary fibrosis (IPF).

Why it matters

Persistent fibroblast activation and senescence are hallmarks of age-related fibrotic diseases like IPF. These findings suggest that targeting the p38 MAPK signaling pathway could have therapeutic potential for treating these debilitating conditions by interrupting the epigenetically reinforced profibrotic program in aging lung cells.

The details

The study, led by researchers at Eastern Virginia Medical School and Old Dominion University, used both IMR90 lung fibroblasts at low and high population-doubling levels as well as primary IPF fibroblasts. They found that while TGF-β1 upregulated profibrotic genes in both young and near-senescent cells, the high-PDL (near-senescent/senescent) fibroblasts exhibited a delayed but sustained p38 MAPK response to TGF-β1. Importantly, pharmacological inhibition of p38 MAPK (with the compound SB202190) blunted profibrotic gene transcription and reduced H4K16 acetylation enrichment at the α-SMA and Col3A1 promoters, indicating an epigenetic mechanism linking p38 signaling to fibrotic gene activation.

  • The study was published on March 3, 2026 in the journal Aging-US.
  • The research was conducted between 2024-2026.

The players

Shan Zhu

Lead author of the study from the Department of Biomedical and Translational Sciences at Eastern Virginia Medical School.

Yan Y Sanders

Corresponding author of the study from the Department of Biomedical and Translational Sciences at Eastern Virginia Medical School and the Macon & Joan Brock Virginia Health Sciences at Old Dominion University.

IMR90 lung fibroblasts

A cell line used in the study to model young and near-senescent lung fibroblasts.

Primary IPF fibroblasts

Fibroblasts isolated directly from patients with idiopathic pulmonary fibrosis and used in the study.

SB202190

A pharmacological inhibitor of the p38 MAPK signaling pathway used in the study.

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What they’re saying

“These findings suggest that a p38 MAPK–dependent epigenetic mechanism is involved in fibroblast activation, supporting the therapeutic potential of p38 MAPK inhibition for treating age-related fibrotic diseases such as IPF.”

— Yan Y Sanders, Corresponding author (Aging-US)

What’s next

The authors outline several key next steps for this research, including determining the upstream triggers that sustain p38 signaling in near-senescent fibroblasts, mapping the chromatin-level events downstream of p38 that maintain H4K16 acetylation at profibrotic promoters, and evaluating p38 inhibition in animal models of age-related pulmonary fibrosis. They also recommend exploring whether epigenetic modulators that reverse H4K16 acetylation can synergize with kinase inhibition to restore repair capacity without impairing normal tissue healing.

The takeaway

This study provides important insights into the epigenetic mechanisms by which the p38 MAPK signaling pathway drives fibrotic gene expression in aging lung cells, offering a potential therapeutic target for treating devastating age-related fibrotic diseases like idiopathic pulmonary fibrosis.